The majority of currently available antidepressants can be classified in 3 classes:                1. monoamine oxidase inhibitors (MAOIs),        2. biogenic amine neurotransmitter [serotonin (5-HT), norepinephrine (NE) and dopamine (DA)] transporter reuptake blockers, and        3. modulators, especially blockers of one or more of the 5-HT and/or NE receptors.        
Since depression is associated with a relative deficiency of the biogenic amines, the use of 5-HT and/or NE-receptor blockers (i.e. 5-HT and or NE-antagonist's) have not proven very successful in the treatment of depression and anxiety and the preferred and currently most efficacious treatments are based on the enhancement of 5-HT and/or NE neurotransmission by blocking their reuptake back from the synaptic cleft (Slattery, D. A. et al., “The evolution of antidepressant mechanisms”, fundamental and Clinical pharmacology, 2004, 18, 1-21; Schloss, P. et al, “new insights into the mechanism of antidepressant therapy”, Pharmacology and therapeutics, 2004, 102, 47-60).
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they generally are effective, well tolerated and have a favourable safety profile compared to the classic tricyclic antidepressants. Drugs claimed to be SSRIs are for example fluoxetine, sertraline and paroxetine.
However, clinical studies on depression indicate that non-response to the known SSRIs is substantial, up to 30%. Another, often neglected, factor in the treatment of depression is the delay in the onset of the therapeutic effect of the SSRIs. Sometimes symptoms even worsen during the first weeks of treatment. Furthermore, sexual dysfunction is generally a side effect common to SSRIs. Accordingly, there is a desire for the development of compounds capable of improving the treatment of depression and other diseases related to malfunctioning of serotonin.
Dual re-uptake inhibitors providing the combined effect of 5-HT reuptake inhibition and NE (norepinephrine is also named noradrenaline, NA) reuptake inhibition on depression is explored in clinical studies of compounds such as Duloxetine (Wong, “Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate”, Expert Opinion on Investigational Drugs, 1998, 7, 10, 1691-1699) and Venlafaxine (Khan-A et al, 30 “Venlafaxine in depressed outpatients”, Psychopharmacology Bulletin, 1991, 27, 141-144). Compounds having such dual effect are also named SNRIs, “serotonin and noradrenaline reuptake inhibitors”, or NSRIs, “noradrenaline and serotonin reuptake inhibitors”.
Since treatment with the selective NE reuptake inhibitor reboxetine has been shown to stimulate 5-HT neurons and mediate the release of 5-HT in the brain (Svensson,T. et al, J. Neural Transmission, 2004, 111, 127) there might be a synergistic advantage using SNRI's in the treatment of depression or anxiety.
The use of SNRI's have been shown in clinical studies to have a beneficial effect on pain (e.g. Fibromyalgia syndrome, overall pain, back pain, shoulder pain, headache, pain while awake and during daily activities) and especially pain associated with depression (Berk, M. Expert Rev. Neurotherapeutics 2003, 3, 47-451; Fishbain, D. A., et al. “Evidence-based data from animal and human experimental studies on pain relief with antidepressants: A structured review” Pain Medicine 2000 1:310-316).
SNRI's have also been shown in clinical studies to have a beneficial effect in attention deficit hyperactivity disorder (ADHD) (N. M. Mukaddes; Venlafaxine in attention deficit hyperactivity disorder, European Neuropsychopharmacology, Volume 12, Supplement 3, October 2002, Page 421).
Furthermore, SNRI's have been shown to be effective for the treatment of stress urinary incontinence (Dmochowski R. R. et al. “Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence”, Journal of Urology 2003, 170:4, 1259-1263.)
Naranjo, C. et al. “The role of the brain reward system in depression” Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2001, 25, 781-823 discloses clinical and preclinical findings of links between lack of extra cellular dopamine in the mesocorticolimbic system and anhedonia, which is one of the main symptoms of depression.
Wellbutrin (bupropion) which has DA re-uptake activity in vitro and in vivo, shows antidepressant efficacy. Other combination studies have indicated that addition of some affinity at the DA uptake site may have some clinical benefit (Nelson, J. C. J. Clin. Psychiatry 1998, 59, 65; Masand, P. S. et al. Depression Anxiety 1998, 7, 89; Bodkin, J. A et al. J. Clin. Psychiatry 1997, 58, 137).
Axford L. et al. (2003, Bioorganic & Medical Chemistry Letters, 13, 3277-3280: “Bicyclo[2.2.1.]heptanes as novel triple re-uptake inhibitors for the treatment of depression”) describe the development of triple 5-HT, NE and DA re-uptake inhibitors for treatment of depression. The combination of an SSRI and a norepinephrine and dopamine reuptake inhibitor, has been shown to have better efficacy in SSRI-non-responders (Lam R. W. et al. “Citalopram and Bupropion-SR: Combining Versus Switching in Patients With Treatment-Resistant Depression.” J. Clin. Psychiatry 2004, 65, 337-340).
There is clinical evidence suggesting that the combination of an SSRI and a norepinephrine and dopamine reuptake inhibitor induces less sexual dysfunction, than treatment with SSRI's alone (Kennedy S. H. et al. “Combining Bupropion SR With Venlafaxine, Paroxetine, or Duloxetine: A Preliminary Report on Pharmacokinetic, Therapeutic, and Sexual Dysfunction Effects” J. Clin. Psychiatry 2002, 63, 181-186).
Diphenyl sulphides of formula I and variations thereof have been disclosed as serotonin re-uptake inhibitors and have been suggested for use in treatment of depression, cf. e.g. WO03029232(A1).

Diphenyl sulphides of formula II and variations thereof have been disclosed as serotonin re-uptake inhibitors and have been suggested for use in treatment of depression, cf. e.g. U.S. Pat. Nos. 5,095,039, 4,056,632, EP 396827 A1 and WO 9312080. EP 402097 describes halogen substituted diphenylsulfides claimed to be selective serotonin inhibitors for treatment of depression. Likewise WO 9717325 disclose derivatives of N,N-dimethyl-2-(arylthio)benzylamine claimed to be selective serotonin transport inhibitors and suggest their use as antidepressants. J. Jilek et al., Collect. Czeck Chem. Commun. 1989, 54, 3294-3338 also discloses various derivatives of diphenyl sulphides, “phenyl-thio-benzylamines” as antidepressants. Furthermore, diphenyl sulphides are also disclosed in U.S. Pat. No. 3,803,143 and claimed useful as antidepressant.

K. Sindelar et al., (K. Sindelar et al. Collect. Czeck Chem. Commun. 1991, 56, 449-458) disclose compounds of formula III with test for selectivity as 5-HT re-uptake inhibitor and NA re-uptake inhibitor, respectively, for use as antidepressants.

The above-mentioned references do not disclose compounds comprising an benzo[b]furane or benzo[b]thiophene group like the compounds of the present invention.
The present invention provides benzo[b]furane and benzo[b]thiophene derivatives of formula IV which are serotonin reuptake inhibitors. A particular aspect of the invention provides compounds possessing the combined effect of serotonin reuptake inhibition and norepinephrine reuptake inhibition. Another particular aspect of the invention provides compounds possessing the combined effect of serotonin reuptake inhibition and dopamine reuptake inhibition. Furthermore, some of the compounds are also triple 5-HT, NE and DA re-uptake inhibitors.
